As a clinician trained in China, I have a long stand interests in biomedical sciences, particularly basic and translational biology, which are stemmed from my personal experiences. First, my mother is a survival of renal carcinoma and my cousin's wife died from pancreatic cancer. Second, I had seen anxiety, sense of loss, frustration, and grief from patients or family when accompanying my mother to the hospital for treatment of her Postphlebitic syndrome and during my clinical training in hospitals in China. Third, I remembered despairingly that whatever we do, we're never going to be able to help families like that in the caring of terminally ill patients in my clinical curriculum. After receiing extensive training in basic biology, both in Dr. Pier Paolo Pandolfi's lab and Dr. Ronald DePinho's lab, I strongly believe that we should not only have a better understanding the basic biology underlying cancer biology, but also make an endeavor to bridge the gap between the basic research and clinical medicine using the translational approach. The proposed study is to explore novel therapeutic opportunities to cure prostate cancer, including castration resistant prostate cancer (CRPC) by explore the tumor-intrinsic and -extrinsic mechanism underlying prostate tumor progression and castration resistance. Particularly, I will focus on biology of MDSCs and the tumor- MDSCs crosstalk. Prostate cancer (PCa) is the most common noncutaneous malignancy in men in the United States and the mainstay therapy for PCa is androgen deprivation therapy, which ultimately failed and results in the development of CRPC. My unpublished results shows that mouse prostate tumors deficient for Pten and Smad4 not only became resistant to surgical castration and a comprehensive AR signaling blockage using surgical castration plus Enzalutamide, a recently approved AR inhibitor for metastatic CRPC. In addition, MDSCs are the predominant sub-population in the intratumoral infiltrated immune cells and anti-Gr1 neutralizing antibody MDSCs depletion in our mouse model lead to a dramatic regression of tumors. Thus I propose to study the role of MDSCs in prostate tumor progression and castration resistance in our mouse model. With Aim1, I will characterize the MDSCs during tumor progression and in the response to ADT. I will also test whether MDSCs are necessary and sufficient for tumor progression by using pharmacological inhibition and genetic depletion of MDSCs. Moreover, I will test whether MDSCs depletion in combination with ADT provides a prolonged therapeutic benefit. In Aim 2, I will perform molecular profiling and bioinformatic analysis to shed light on the mechanistic insight on the MDSCs-tumor crosstalk. Thus I will explore the possibility to target the MDSCs-tumor crosstalk in order to treat prostate caner and castration resistance. So in Aim 3, I will first perform functional validations of the candidate genes identified from Aim 2 using gain-of- function and loss-of-function approaches in multiple assays. Furthermore, I will validate the genes identified from our mouse model in human prostate cancer samples for their potential used as biomarkers as well as potential therapeutic targets. The information obtained from this aim will help us This proposed study would help me to form a strong research program, with which I will launch an independent faculty position in an academic/medical research institution. To that end, my immediate goals are to continue sharpening my technical skills in mouse genetics, cancer immunology, tumor microenvironment and expanding my skills in cancer immunotherapy, oncogenomics, biostatistics and translational biology. In terms of my career development, I will devote to improve my skills on managing lab, mentoring postdocs and students, scientific writing and presentation, and seeking for collaborations, among others, because these skills are all essential for me to land a faculty position and succeed as a PI. MD Anderson Cancer Center (MDACC) and the Ronald DePinho laboratory provide an excellent training environment for me to achieve these goals. Even though Dr. DePinho is President of MDACC now, he still promises to devote 2.5% effort to my training and career development. I have also formed an extraordinary advisory committee composed of Dr. Mien-Chie Huang, and Dr. Giulio Draetta. They will not only provide me technical support for my proposed study, but also guide me to look for a faculty position and succeed as an independent investigator. With the help of K99/R00 training grant, I will have a good start to achieve my long term goals, which are to continue exploring basic and translational problems in cancer biology, including prostate cancer progression and castration resistance, as a lab head in an academic/medical research institute and to contribute to developing novel cancer therapies as a team player by collaborating with other scientists, physicians and pharmaceutical companies.